Dr Kristina Cook
School of Medical Sciences, FMH
University of Sydney
Dr Kristina Cook is a biologist and research fellow at the Charles Perkins Centre. Her lab studies how cells respond and adapt to reduced oxygen, with a focus on oxygen sensing pathways in cancer (particularly brain cancers like glioblastoma and DIPG/DMG), sleep and cardiovascular disease. Dr Cook has a multi-disciplinary background in molecular and cell biology, drug development, high-throughput screening and rational drug design.
My research focuses on how cells adapt to low oxygen levels (hypoxia) and how this drives disease progression, particularly in cancers. By studying the enzymes and pathways involved in oxygen sensing, our goal is to uncover new therapeutic strategies to inhibit these processes and develop innovative treatments.
Why Oxygen Matters in Disease
Oxygen is vital for life, and cells have evolved ways to detect and respond to low oxygen. These responses help cells adapt, both in the short and long term, but can also worsen diseases. For instance, when exposed to hypoxia, cells adjust their metabolism to use less oxygen. In aggressive brain tumors like glioblastoma, this adaptation promotes tumor invasion and resistance to treatments like chemotherapy and radiation, leading to poorer outcomes for patients.
Exploring Cellular Oxygen Sensing Mechanisms
In my lab, we study how cells sense and respond to hypoxia in tumors, which are frequently oxygen-deprived, and in other diseases marked by low oxygen levels. One of the best-known pathways involved is the hypoxia-inducible factor (HIF) pathway, which is regulated by oxygen-sensing enzymes called PHD and FIH. The importance of this discovery was highlighted by the awarding of the 2019 Nobel Prize in Physiology or Medicine (read more here:Nobel Prize 2019 Summary). We focus on understanding how HIF is regulated in cancer and other diseases and work on developing small molecules that can inhibit HIF activity as a potential treatment.
Discovering New Oxygen Sensing Pathways
Beyond HIF, we are interested in other recently identified oxygen sensors that influence cell behavior. These new sensors, like histone demethylases (KDMs) and 2-aminoethanethiol dioxygenase (ADO), could be just as important as HIF in controlling how cells react to hypoxia.
Many of the genes encoding oxygen sensors are mutated or altered in brain cancers, and we aim to understand how these genetic changes, combined with hypoxia, drive tumor growth. This research has clinical implications, and we collaborate with other scientists and clinicians to identify mRNA and imaging signatures of hypoxia in brain tumors and other cancers.
Understanding Different Forms of Hypoxia
Not all hypoxia is the same. Our work also explores how cells respond to different types of hypoxia—acute, chronic, and intermittent—conditions that arise in diseases like cancer, sleep apnea, and heart failure. Different oxygen sensors react to these forms of hypoxia in distinct ways, and we aim to uncover how these varied responses occur using ourphysiological models of hypoxia.
See our paper on how the interaction between HIF and the histone demethylase KDM4 can fine tunes the response to hypoxia.
Brain Tumor Metabolism and Its Relationship to Hypoxia
Brain tumors, including glioblastomas and DIPG, often rely on altered metabolic pathways, such as increased mitochondrial activity or glycolysis, to thrive in low-oxygen environments. These metabolic changes not only fuel tumor growth but also contribute to resistance against standard treatments like radiation and chemotherapy. By understanding the link between hypoxia and tumor metabolism, we aim to identify new metabolic vulnerabilities that could be targeted to improve therapeutic outcomes for patients with these aggressive brain tumors.
One approach we are trialling is using drugs to target mitochondrial oxidative phosphorylation (OXPHOS). In preclinical models of DIPG, we've shown that inhibiting OXPHOS reduces hypoxia and increases the radiosensitivity of DIPG cells: see our research paper here.
Check out one of our review papers on the topic.
Broader Interests in Cellular Metabolism and Hypoxia
We are also interested in the broader relationship between cellular metabolism and hypoxia across various diseases. Metabolism is regulated by oxygen levels, and cells adapt their energy production processes when oxygen is limited. These adaptations can either support normal cellular function or contribute to disease progression, as seen in cancer, cardiovascular disease, sleep and metabolic disorders.
Circadian Rhythms and Hypoxia in Brain Tumors
A growing area of interest in our lab is the relationship between circadian rhythms (the body’s natural biological clock) and hypoxia, particularly in brain tumors like adult glioblastoma and pediatric diffuse intrinsic pontine glioma (DIPG). We are investigating how hypoxia can disrupt circadian rhythms to influence tumor growth and response to treatment.
See our review here:https://journals.physiology.org/doi/full/10.1152/ajpcell.00305.2020
Cancer Biology
Molecular and Cellular Biology
- Franklin Women Teresa Anderson Award (2021).
- Exceptional Contribution Award, Charles Perkins Centre (2019).
- Professor Tony Basten Fellowship. Sydney Medical School (2018).
- Best Poster and Mini-Oral Presentation Award, Australasian Sleep Association (2018).
- AMP Tomorrowmaker Award (2017).
- Cancer Institute NSW Early Career Fellowship (2017-2020).
- University of Sydney Fellowship (2017).
- Females in Science award (2016). Bank of Queensland and Centenary Institute.
- Career Advancement Award (2015). UNSW.
- AACR Busch Scholar in Training award (2008)
- NIH/NCI Director’s Innovation Award (2007) with Dr William D Figg.
- NIH OxCam Biomedical Research Scholar award
| Project title | Research student |
|---|---|
| Understanding the Role of Enzymatic Oxygen Sensors in the Cellular Response to Hypoxia in Disease | Neha BAL |
Publications
Book Chapters
- Cook, K., Schofield, C. (2008). Therapeutic strategies that target the HIF system. In WD Figg, & J Folkman (Eds.), Angiogenesis: An Integrative Approach From Science to Medicine, (pp. 359-373). Boston: Springer. [More Information]
Journals
- Patel, K., Jiramongkol, Y., Norman, A., Maxwell, J., Mohanty, B., Payne, R., Cook, K., White, M. (2024). The enzymatic oxygen sensor cysteamine dioxygenase binds its protein substrates through their N-termini. Journal of Biological Chemistry, 300(9), 107653. [More Information]
- Sutherland, K., Sadr, N., Bin, Y., Cook, K., Dissanayake, H., Cistulli, P., De Chazal, P. (2022). Comparative associations of oximetry patterns in Obstructive Sleep Apnea with incident cardiovascular disease. Sleep, 45(12.0). [More Information]
- Mudassar, F., Shen, H., Cook, K., Hau, E. (2022). Improving the synergistic combination of programmed death-1/programmed death ligand-1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment. Journal of Medical Imaging and Radiation Oncology, 66(4), 560-574. [More Information]
Conferences
- De Chazal, P., Sadr, N., Dissanayake, H., Cook, K., Sutherland, K., Bin, Y., Cistulli, P. (2021). Predicting Cardiovascular Outcomes Using the Respiratory Event Desaturation Transient Area Derived from Overnight Sleep Studies. 43rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2021, Mexico: Institute of Electrical and Electronics Engineers (IEEE). [More Information]
- Sadr, N., Bin, Y., Sutherland, K., Cook, K., Dissanayake, H., Cistulli, P., De Chazal, P. (2020). Is Cumulative Time of Oxygen Desaturation a Better Predictor of Cardiovascular Mortality than Apnoea Hypopnoea Index? 42nd Annual International Conferences of the IEEE Engineering in Medicine and Biology Society (EMBC 2020), : Springer Verlag. [More Information]
2024
- Patel, K., Jiramongkol, Y., Norman, A., Maxwell, J., Mohanty, B., Payne, R., Cook, K., White, M. (2024). The enzymatic oxygen sensor cysteamine dioxygenase binds its protein substrates through their N-termini. Journal of Biological Chemistry, 300(9), 107653. [More Information]
2022
- Sutherland, K., Sadr, N., Bin, Y., Cook, K., Dissanayake, H., Cistulli, P., De Chazal, P. (2022). Comparative associations of oximetry patterns in Obstructive Sleep Apnea with incident cardiovascular disease. Sleep, 45(12.0). [More Information]
- Mudassar, F., Shen, H., Cook, K., Hau, E. (2022). Improving the synergistic combination of programmed death-1/programmed death ligand-1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment. Journal of Medical Imaging and Radiation Oncology, 66(4), 560-574. [More Information]
- Martinez, C., Jiramongkol, Y., Bal, N., Alwis, I., Nedoboy, P., Farnham, M., White, M., Cistulli, P., Cook, K. (2022). Intermittent hypoxia enhances the expression of hypoxia inducible factor HIF1A through histone demethylation. Journal of Biological Chemistry, 298(11). [More Information]
2021
- Dutta, S., Li, D., Wang, A., Ishak, M., Cook, K., Farnham, M., Dissanayake, H., Cistulli, P., Hunyor, I., Liu, R., Wilcox, I., Koay, Y., Yang, J., Lal, S., O'Sullivan, J. (2021). Metabolite signatures of heart failure, sleep apnoea, their interaction, and outcomes in the community. ESC Heart Failure, 8(6), 5392-5402. [More Information]
- De Chazal, P., Sadr, N., Dissanayake, H., Cook, K., Sutherland, K., Bin, Y., Cistulli, P. (2021). Predicting Cardiovascular Outcomes Using the Respiratory Event Desaturation Transient Area Derived from Overnight Sleep Studies. 43rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2021, Mexico: Institute of Electrical and Electronics Engineers (IEEE). [More Information]
- Cook, K., Shen, H., McKelvey, K., Gee, H., Hau, E. (2021). Targeting glucose metabolism of cancer cells with dichloroacetate to radiosensitize high-grade gliomas. International Journal of Molecular Sciences, 22(14), 7265-1-7265-15. [More Information]
2020
- Oehlers, S., Hortle, E., Cook, K. (2020). A zebrafish model of tuberculosis comorbidity and the effects of HIF-activating intervention. FEBS Journal, 287(18), 3917-3920. [More Information]
- Shen, H., Cook, K., Gee, H., Hau, E. (2020). Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas. Journal of Experimental and Clinical Cancer Research, 39(1), 1-14. [More Information]
- Sadr, N., Bin, Y., Sutherland, K., Cook, K., Dissanayake, H., Cistulli, P., De Chazal, P. (2020). Is Cumulative Time of Oxygen Desaturation a Better Predictor of Cardiovascular Mortality than Apnoea Hypopnoea Index? 42nd Annual International Conferences of the IEEE Engineering in Medicine and Biology Society (EMBC 2020), : Springer Verlag. [More Information]
2019
- Martinez, C., Cistulli, P., Cook, K. (2019). A Cell Culture Model that Mimics Physiological Tissue Oxygenation Using Oxygen-permeable Membranes. Bio-protocol, 9(18), 1-14. [More Information]
- Kataria, N., Martinez, C., Kerr, B., Zaiter, S., Morgan, M., McAlpine, S., Cook, K. (2019). C-Terminal HSP90 Inhibitors Block the HIF-1 Hypoxic Response by Degrading HIF-1alpha through the Oxygen-Dependent Degradation Pathway. Cellular Physiology and Biochemistry, 53(3), 480-495. [More Information]
- Cook, K. (2019). Determining the Redox Potential of a Protein Disulphide Bond. Methods in Molecular Biology, 1967, 65-86. [More Information]
2018
- Butera, D., Passam, F., Ju, A., Cook, K., Woon, H., Aponte-Santamaria, C., Gardiner, E., Davis, A., Murphy, D., Bronowska, A., Jackson, S., Hogg, P., et al (2018). Autoregulation of von Willebrand factor function by a disulfide bond switch. Science Advances, 4(2), 1-12. [More Information]
- Hunyor, I., Cook, K. (2018). Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 315(4), R669-R687. [More Information]
- Harris, E., Strope, J., Beedie, S., Huang, P., Goey, A., Cook, K., Schofield, C., Chau, C., Cadelis, M., Copp, B., et al (2018). Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models. Marine Drugs, 16(7), 241. [More Information]
2017
- Read, S., O'Connor, K., Suppiah, V., Ahlenstiel, C., Obeid, S., Cook, K., Cunningham, A., Douglas, M., Hogg, P., Booth, D., George, J., Ahlenstiel, G. (2017). Zinc is a potent and specific inhibitor of IFN-(lambda)3 signaling. Nature Communications, 8, 1-15. [More Information]
2016
- Bekendam, R., Bendapudi, P., Lin, L., Nag, P., Pu, J., Kennedy, D., Feldenzer, A., Chiu, J., Cook, K., Furie, B., Hogg, P., et al (2016). A substrate-driven allosteric switch that enhances PDI catalytic activity. Nature Communications, 7, 1-11. [More Information]
- Goey, A., Chau, C., Sissung, T., Cook, K., Venzon, D., Castro, A., Ransom, T., Henrich, C., McKee, T., et al (2016). Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1alpha/p300 Interaction. Journal of Natural Products, 79(5), 1267-1275. [More Information]
2015
- Jayatunga, M., Thompson, S., McKee, T., Chan, M., Reece, K., Hardy, A., Sekirnik, R., Seden, P., Cook, K., et al (2015). Inhibition of the HIF1alpha-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II). European Journal of Medicinal Chemistry, 94, 509-516. [More Information]
- Chan, S., Patel, P., Ransom, T., Henrich, C., McKee, T., Goey, A., Cook, K., Figg, W., McMahon, J., et al (2015). Structural Elucidation and Synthesis of Eudistidine A: An Unusual Polycyclic Marine Alkaloid that Blocks Interaction of the Protein Binding Domains of p300 and HIF-1alpha. Journal of the American Chemical Society, 137(16), 5569-5575. [More Information]
2014
- Butera, D., Cook, K., Chiu, J., Wong, J., Hogg, P. (2014). Control of blood proteins by functional disulfide bonds. Blood, 123(13), 2000-2007. [More Information]
- Reece, K., Richardson, E., Cook, K., Campbell, T., Pisle, S., Holly, A., Venzon, D., Liewehr, D., Chau, C., et al (2014). Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1alpha/p300 complex in a preclinical model of prostate cancer. Molecular Cancer, 13(1), 1-12. [More Information]
2013
- Cook, K., McNeil, H., Hogg, P. (2013). Allosteric control of betaII-tryptase by a redox active disulfide bond. Journal of Biological Chemistry, 288(48), 34920-34929. [More Information]
- Cook, K., Hogg, P. (2013). Post-translational control of protein function by disulfide bond cleavage. Antioxidants & Redox Signaling, 18(15), 1987-2015. [More Information]
2010
- Cook, K., Figg, W. (2010). Angiogenesis inhibitors: Current strategies and future prospects. CA A Cancer Journal for Clinicians, 60(4), 222-243. [More Information]
2009
- Cook, K., Hilton, S., Mecinovic, J., Motherwell, W., Figg, W., Schofield, C. (2009). Epidithiodiketopiperazines Block the Interaction between Hypoxia-inducible Factor-1 alpha (HIF-1 alpha) and p300 by a Zinc Ejection Mechanism. Journal of Biological Chemistry, 284(39), 26831-26838. [More Information]
2008
- Cook, K., Schofield, C. (2008). Therapeutic strategies that target the HIF system. In WD Figg, & J Folkman (Eds.), Angiogenesis: An Integrative Approach From Science to Medicine, (pp. 359-373). Boston: Springer. [More Information]
Selected Grants
2023
- Using Genomics to Inform Precision Medicine for Autoimmune Disease, Cook K, Charlie Teo Foundation/Teo Research Fellowship
2020
- The Role of Hypoxia Inducible Factor in the Development of Heart Failure, Cook K, NSW Health/Early Mid-Career Researcher Grant
In the media
- December 2023:Dr Cook's Brain Cancer Research
- March 2020:World Sleep Day Interview with Dr Cook
- November 2017:AMP Tomorrow Makers announced for 2017
- August 2017:International search for future research leaders, Fellowships for outstanding early-career researchers
- February 2017:Early career female researchers shine in cancer fellowships
- November 2016:11 outstanding early career researchers join the University: 2017 University of Sydney Fellows announced.
- November 2017:Cancer researcher wins AMP Tomorrow Makers award
